Background: Histoplasmosis is the most common of the endemic mycoses and a major cause of morbidity and mortality in patients living in endemic areas. Histoplasma capsulatum first was described in 1905 by Samuel Darling, a US Army pathologist stationed in Panama. Darling examined visceral tissues and bone marrow from a young man from Martinique whose death originally was attributed to miliary tuberculosis. The organism initially was described as protozoal. Because it lacked a kinetoplast, Darling assumed that it was a different species of Leishmania. He termed it H capsulatum.

In 1912, after reviewing tissue specimens, da Rocha-Lima suggested that the organism resembled a yeast rather than a protozoan. Subsequently, H capsulatum has been found worldwide. In the United States, histoplasmosis is highly prevalent in the Ohio and Mississippi River valleys.

Pathophysiology: The respiratory tract is considered the portal of entry for H capsulatum in most patients. Cellular immunity plays the primary role in defense against the organism. After conidia have been inhaled and settle into the alveoli, they bind to the CD2/CD18 family of integrins and are engulfed by both neutrophils and macrophages but not killed.

In the macrophages, conidia transform into yeast within the pulmonary parenchyma; the yeast migrates, presumably intracellularly, to local draining lymph nodes and, subsequently, to distant organs rich in mononuclear phagocytes, such as the liver and spleen. The transition from the mycelial to the yeast phase is one of the most critical determinants for establishing infection. Cellular immunity to Histoplasma develops within 2 weeks of exposure. These defense mechanisms are sufficient to control the infection in immunocompetent subjects, explaining the subclinical or self-limited course characteristic of acute histoplasmosis.

Yeast grows more rapidly within macrophages from HIV-infected individuals or within macrophages infected in vitro with a macrophage-tropic strain of HIV. Among T-cell populations, CD4 cells are vitally important, as demonstrated by Gomez when mice deficient in CD4 cells died when challenged with a sublethal inoculum of yeast.

The hallmark of tissue response to this fungus is the development of caseating and/or noncaseating granulomas in which calcium may be deposited. Granulomas consist of an admixture of mononuclear phagocytes and lymphocytes, principally T cells. The putative function of the granuloma is to contain fungal growth. Progressive clinically evident dissemination occurs primarily in patients with underlying immunosuppressive disorders, those at the extreme ranges of age, and/or in patients who have experienced an unusually heavy exposure.

Frequency:

• In the US: The infection is most common in the southeastern, mid-Atlantic, and central states and in the Ohio and Mississippi River valleys.

• Internationally: H capsulatum is endemic in areas of North and Latin America but can be found throughout the world. The conditions that favor the growth of this fungus in soil typically are found in the temperate zone between latitudes 45° north and 30° south. Factors accounting for its geographic distribution include humid environmental conditions and acidic permeable soil. The organism commonly is found in bird and bat droppings, most often where guano is decaying and mixed with soil.

Mortality/Morbidity: Only 5% of infected individuals develop symptomatic disease after a low-level exposure to Histoplasma. The estimated incidence of histoplasmosis is 1 per 2000 persons.

After two Indianapolis epidemics, 8% of clinically recognized cases of histoplasmosis developed progressive disseminated histoplasmosis (PDH). In the two epidemics, the primary risk factors for this manifestation of histoplasmosis were age older than 54 years and immunosuppression.

Among patients with AIDS, the incidence may approach 25%. When the condition is untreated, the mortality rate is almost 100%. Before effective antifungal agents were introduced, most children died within 5-6 weeks of symptom onset.

Race: In histoplasmosis, unlike coccidioidomycosis, no differences are known in susceptibility or resistance to infection among racial or ethnic groups.

Sex: Male-to-female ratio is approximately 4:1. The higher frequency in men probably is correlated to a higher incidence of smoking.

Age: Clinical disease more commonly occurs in older persons and those younger than 2 years.

Clinical Details: The clinical spectrum of the disease depends on the extent of exposure, age, presence of underlying lung disease, general immune status, and specific immunity to H capsulatum. Lungs are the most common organs involved. Infections can be classified as follows:

• Pulmonary histoplasmosis

   

  • Acute asymptomatic pulmonary histoplasmosis: This is the most common manifestation that occurs following histoplasmosis infection (>90%). This type commonly occurs in individuals with normal immunity residing in endemic areas. Patients develop positive skin tests but most have normal chest radiographs and negative serology tests.

     

  • Acute symptomatic pulmonary histoplasmosis: This is a benign, self-limited illness characterized by symptoms of fever, chills, headache, cough, and retrosternal or pleuritic chest pain. Malaise, weakness, fatigue, and myalgia are observed in a distinctly smaller percentage of patients. Symptoms commonly are mistaken for a flulike illness; however, coryza and sore throat are not typical symptoms of histoplasmosis and suggest alternative diagnoses. Physical examination usually is unremarkable except for fever. Rales may be detected and, rarely, hepatosplenomegaly. Symptoms typically develop 2-4 weeks after infection depending on the intensity of exposure and immunity status of the patient and typically resolve within several weeks.

     

  • Acute reinfection pulmonary histoplasmosis: This is not uncommon in those residing in endemic areas and subject to re-exposure. The duration of illness often is shorter than in primary infection. The characteristic chest radiogram shows numerous small nodules diffusely scattered throughout both lung fields.

     

  • Chronic pulmonary histoplasmosis: This occurs in patients with underlying lung disease, especially chronic obstructive pulmonary disease (COPD). Affected patients develop a productive cough, dyspnea, chest pain, fatigue, fever, and sweats and have fibrotic apical lesions with cavitation on chest radiographs or CT. The clinical and radiographic findings resemble those seen in reactivation tuberculosis; the two syndromes often are confused, and incorrect diagnoses have resulted in inappropriate treatment.

   

• Progressive disseminated histoplasmosis (PDH): It occurs in immunodeficient patients with defective T-cell immunity (due to AIDS, hematologic malignancies [eg, Hodgkin and non-Hodgkin lymphoma], or those taking immunosuppressive medications). Patients at the extreme of ages also are at risk for disseminated disease. PDH can develop upon re-exposure to a large inoculum of the fungus or upon reactivation of dormant endogenous foci. Most cases are believed to arise from endogenous reactivation since the disease develops in those who reside in remote endemic areas. Fever and malaise are the two most common manifestations, followed by weight loss, cough, and diarrhea. Patients can develop hepatosplenomegaly, lytic bone lesions, skin lesions, peripheral lymphadenopathy, prostatitis, or epididymitis.

   

• Miliary pulmonary histoplasmosis: This is a special presentation that follows a more intense exposure. Patients often develop reticulonodular or miliary pulmonary infiltrates (a scenario that resembles miliary tuberculosis) and may progress to respiratory failure or extrapulmonary) PDH (see Image 6, Image 7).

   

• Nonpulmonary histoplasmosis

   

  • Pericarditis occurs in 5-10% of symptomatic cases of acute histoplasmosis; it is caused by an immunologic reaction to histoplasmosis in the adjacent mediastinal lymph nodes.

     

  • Rheumatologic syndromes, such as arthralgias, erythema nodosum, and erythema multiforme, are present in approximately 6% of patients, most of whom are women. In some patients, this manifestation of histoplasmosis may be the presenting complaint. Frank arthritis is distinctly uncommon.

     

  • Sarcoidosislike syndrome is so termed because distinguishing between histoplasmosis and Sarcoidosis can be difficult. Both may demonstrate similar histopathologic features and serum angiotensin-converting enzyme levels are elevated in both. Therefore, for patients presenting with mediastinal or hilar lymphadenopathy and residing or recently residing in an endemic region, it is critically important to consider histoplasmosis in the differential diagnosis.

   

• African histoplasmosis

   

  • H capsulatum var duboisii is a variant that primarily is seen in Africa; however, a few cases have been reported in the United States and Chile. The yeast form of H capsulatum var duboisii typically is much larger, with a diameter as large as 15 mm, and has a thicker wall.

     

  • The clinical picture associated with infection by H capsulatum var duboisii is distinctly different from that associated with H capsulatum var capsulatum.

     

  • Skin and the skeleton are affected the most frequently by this pathogen. Skin ulcers, nodules, and psoriasislike lesions are common. Osteolytic bone lesions are noted in as many as 50% of patients. The skull and ribs are the bones affected the most frequently, followed by the vertebrae. The organism produces granulomatous inflammation within the bone. Pulmonary involvement is uncommon, even in the presence of dissemination.

Complications of histoplasmosis infection

• Mediastinal granuloma: It is an uncommon late sequelae of mediastinal adenitis characterized by massive enlargement of the mediastinal lymph nodes that become encapsulated and caseous centrally. A consequence of enlarged nodes is the creation of sinuses or fistulas between the airways and the pericardium or esophagus. There is no associated fibrotic reaction. Extrinsic compression of the trachea can cause respiratory distress, especially in young children, and prolonged obstruction can cause bronchiectasis or bronchial stenosis.

   

• Fibrosing mediastinitis: Represents an excessive fibrotic response to a prior episode of histoplasmosis in which almost all mediastinal structures can be involved. It is postulated to occur as a result of leakage of antigen from caseous nodes into the mediastinum, which stimulates an abnormal immunologic/inflammatory response leading ultimately to fibrosis. The fibrosis can constrict or obstruct mediastinal structures such as SVC, pulmonary arteries or veins, the bronchi, and the esophagus. Affected patients usually are young and can be asymptomatic. However, symptoms commonly develop gradually as the mediastinal structures are obliterated, causing cough, dyspnea, SVC syndrome, dysphagia, hemoptysis, and hoarseness. It is associated with higher morbidity and mortality and is less amenable to treatment.

   

• Broncholithiasis: When lymph nodes and pulmonary granulomas calcify, they can erode into the adjacent bronchi, causing hemoptysis and/or obstruction. Patients can expectorate rocklike particles of tissue, which can result in recurrent and severe hemoptysis, bronchial obstruction, or tracheoesophageal fistula.

   

• Cavitary pulmonary histoplasmosis: Patients can develop progressive upper lobe infiltrates with cavitation, which indicates disease progression. Men older than 50 years with preexisting chronic lung disease (usually emphysema) constitute the highest proportion of patients. This disease is unusual in patients younger than age 40 years (<5% of all cases).

Preferred Examination: Diagnostic modalities include cultures, fungal stains of tissue or body fluids, and tests for antibodies and antigens. Each test has limitations that must be recognized to be used correctly. The success rate varies considerably and often is correlated with the number of specimens collected, the source of the specimen, and the burden of infection.

Antigen detection

Antigen is detected in as many as 90% of patients with PDH, 40% with cavitary disease, and 20% with acute pulmonary histoplasmosis. Histoplasma glycoprotein antigen can be detected in the urine of 90% of patients with disseminated infection and in 75% of those with diffuse acute pulmonary histoplasmosis. The sensitivity of antigen detection is lower in serum than in urine and the highest diagnostic yield can be achieved by testing both specimens.

The test has excellent usefulness for monitoring relapses of PDH, especially in patients with immunosuppression. Antigen detection is much more sensitive than serology for identifying relapses and has been applied successfully to cerebrospinal fluid in patients with meningitis. Antigen levels fall with successful therapy and increase with relapse. The specificity of this test also is relatively good; however, in patients infected with Blastomyces dermatitidis, Paracoccidioides brasiliensis, or Penicillium marneffei, a high degree of cross reactivity exists in the enzyme-linked immunosorbent assay urine antigen test.

Serology

Serologic tests are positive in approximately 80% of patients with disseminated histoplasmosis, 90% with acute pulmonary histoplasmosis, and almost 100% of patients with chronic pulmonary histoplasmosis. A high serum concentration of antibodies develops within 8 weeks of exposure in most patients and then declines to low or undetectable levels over a 2- to 5-year period.

The complement fixation test is more sensitive than the immunodiffusion test. Complement fixation titers of 1:32 or higher are highly suggestive of acute infection. False-positive results may occur in blastomycosis, coccidioidomycosis, candidiasis, and with aspergillosis.

Fungal cultures

Cultures provide the strongest proof for histoplasmosis but are limited by low sensitivity (10-15%) in self-limited infections and by delayed growth (2-4 wk). In patients with disseminated disease, the highest yield is from bone marrow or blood cultures, which are positive in more than 75% of patients.

The organisms can be found in sputum or bronchoscopy specimens in 60-85% of patients with cavitary histoplasmosis. Cultures usually are negative in patients with mild acute pulmonary, pericardial, or rheumatologic manifestations.

Fungal staining

Fungal staining permits rapid diagnosis but with a lower sensitivity than culture or antigen detection. Bone marrow, cerebrospinal fluid, and bronchoalveolar lavage are associated with the highest yields (see Image 1, Image 2). Fungal staining of lung or mediastinal lymph node tissue permits rapid diagnosis of histoplasmosis but has a lower sensitivity than culture or antigen detection. Polymerase chain reaction techniques are in development and may assist in the correct diagnosis of H capsulatum infections in patients in whom morphology is inconclusive and cultures are negative. Histologically, noncaseating granulomata are commonly seen (see Image 3).

Skin test

Skin tests rarely are helpful.

Radiologic modalities

Radiographic findings primarily depend on the type of presentations and the immune status of the host. Although chest radiographic findings are normal in most patients, it is the first radiologic modality performed. The most common abnormal radiographic findings consist of single or multiple poorly defined areas of airspace consolidation frequently in the lower lobes. With time, these opacities are cleared and form a nodule that can later calcify.

DIFFERENTIALS

Blastomycosis, Thoracic
Coccidioidomycosis, Thoracic
Sarcoidosis, Thoracic

Other Problems to be Considered:

Blastomycosis
Coccidioidomycosis
Mycobacterium tuberculosis
Nonmycobacterial tuberculosis
Miliary tuberculosis
Lymphoma
HIV
Sarcoidosis

X-RAY

Findings: Radiographic findings depend primarily on the type of presentations and the immune status of the host.

• Chest radiographic findings are normal in most patients. A solitary pulmonary nodule is a frequent finding on chest radiographs of the patient with asymptomatic primary infection. These nodules vary from a few millimeters to several centimeters. Most of these nodules have well-defined margins and central, laminar, or diffuse calcification patterns. Interestingly, some nodules can slowly enlarge because of continued elaboration of collagen at the periphery of the lesion, thus can be difficult to distinguish from malignancy.

   

• As many as 10-25% of patients with asymptomatic infection develop single or multiple poorly defined areas of airspace consolidation and/or nodules, with or without hilar lymph node enlargement. Enlarged lymph nodes often are seen after an asymptomatic infection. Adenopathy is frequently seen with lung parenchymal abnormalities and often contain calcification. This calcification occasionally may be seen on CT only. Patients with noncalcified mediastinal adenopathy need to be distinguished from sarcoidosis, lymphoma, and metastasis. Enlarged lymph nodes can cause significant bronchial or tracheal compression or obstruction and may cause esophageal obstruction. As a consequence of airway obstruction, atelectasis, collapse, and obstructive pneumonitis can develop.

   

• In acute symptomatic pulmonary histoplasmosis, radiographic findings include areas of air space parenchymal consolidation that involve more than one segment or lobe, simulating acute bacterial pneumonia.

   

• Pleural effusions are seen in a minority of patients with acute pulmonary histoplasmosis and organisms rarely are isolated from pleural fluid.

   

• After heavy exposure, radiographs can show widely disseminated, diffuse, fairly discrete nodular shadows throughout the lungs (with individual lesions measuring 1-10 mm in diameter), termed miliary histoplasmosis (see Image 4, Image 5), a scenario similar to miliary tuberculosis (see Image 6, Image 7). The infiltrates clear within 2-8 months; however, lesions may fibrose and calcificate or persist for many years.

   

• Lung cavitation usually is noted in persons with underlying obstructive lung disease similar to chronic active tuberculosis and is predominantly upper lobe disease characterized by fibrosis, necrosis, cavitation, and granulomatous inflammation.